Дисертації з теми "Multicenter clinical trial"

Objective: To evaluate the safety and effectiveness of round window (RW), oval window (OW), CliP and Bell couplers for use with an active middle ear implant. Methods: This is a multicenter, long-term, prospective trial with consecutive enrollment, involving 6 university hospitals in Germany. Bone conduction, air conduction, implant-aided warbletone thresholds and Freiburger monosyllable word recognition scores were compared with unaided preimplantation results in 28 moderate-to-profound hearing-impaired patients after 12 months of follow-up. All patients had previously undergone failed reconstruction surgeries (up to 5 or more). In a subset of patients, additional speech tests at 12 months postoperatively were used to compare the aided with the unaided condition after implantation with the processor switched off. An established quality-of-life questionnaire for hearing aids was used to determine patient satisfaction. Results: Postoperative bone conduction remained stable. Mean functional gain for all couplers was 37 dB HL (RW = 42 dB, OW = 35 dB, Bell = 38 dB, CliP = 27 dB). The mean postoperative Freiburger monosyllable score was 71% at 65 dB SPL. The postimplantation mean SRT 50 (speech reception in quiet for 50% understanding of words in sentences) improved on average by 23 dB over unaided testing and signal-to-noise ratios also improved in all patients. The International Outcome Inventory for Hearing Aids (IOI-HA) quality-of-life questionnaire was scored very positively by all patients. Conclusion: A significant improvement was seen with all couplers, and patients were satisfied with the device at 12 months postoperatively. These results demonstrate that an active implant is an advantage in achieving good hearing benefit in patients with prior failed reconstruction surgery.

A técnica da remoção seletiva de tecido cariado (RSTC) para lesões de cárie profundas em dentina de dentes decíduos e permanentes, já é consenso na literatura e é sustentada por pesquisas que demonstram excelentes resultados clínicos, radiográficos e microbiológicos. No entanto, a longevidade de restaurações adesivas realizadas após a RSTC, principalmente na dentição decídua, vem gerando algumas dúvidas e preocupações quanto ao seu desempenho, merecendo esclarecimentos. O objetivo deste estudo randomizado, controlado e multicêntrico foi comparar a taxa de sucesso de restaurações adesivas realizadas em dentes decíduos posteriores após a remoção total (RTTC) ou seletiva (RSTC) de tecido cariado ao longo de 30 meses. Métodos: Crianças de 4 a 8 anos de idade portadoras de pelo menos duas lesões cavitadas ativas em metade interna de dentina (metade interna da dentina na avaliação do RX interproximal e com pelo menos 1mm de dentina separando a lesão cariosa da polpa) e que se enquadrassem nos critérios de inclusão e exclusão participaram do estudo. Para cada criança os dentes (no mínimo dois, mas podendo ser mais) foram aleatoriamente divididos de acordo com os seguintes tratamentos: RTTC (grupo controle) ou RSTC (grupo teste). Nos casos em que ocorreu exposição pulpar, o dente foi devidamente tratado e excluído da amostra, os dados em relação ao tipo de remoção de tecido cariado que levou à exposição foram coletados. Quatro instituições participaram do estudo (Universidade Federal do Rio Grande do Sul; Universidade de São Paulo; Universidade Peruana Cayetano Heredia; Universidade Internacional do Equador), resultando em quatro odontopediatras que realizaram os procedimentos de remoção de tecido cariado e posterior restauração em resina composta, avaliadas clinicamente no baseline, 6, 12, 18, 24 e 30 meses. Todos os procedimentos foram realizados sob anestesia local e isolamento absoluto. Características sociodemográficas foram coletadas no baseline e características clínicas como índice ceod/CPOD, índice de placa visível (IPV) e índice de sangramento gengival (ISG) foram coletados em todos os períodos de acompanhamento. Em todos os momentos experimentais foram avaliados os aspectos clínicos das restaurações por um examinador cego e calibrado através do índice FDI adaptado. Para determinar as taxas de sucesso das restaurações de resina composta foram geradas curvas de sobrevida com o estimador Kaplan-Meyer para cada grupo avaliado, assim como as taxas de falha anual das restaurações. O modelo de regressão de Cox com falhas compartilhadas foi realizado para avaliar diferenças nas taxas de sobrevida das restaurações de acordo com o tratamento, instituição e características clínicas e demográficas da amostra. Resultados: Cento e seis crianças (51 meninos e 55 meninas) colaboraram com 278 dentes submetidos a restaurações adesivas, 137 após RTTC e 141 após RSTC. Oito exposições pulpares ocorreram no grupo da RTTC e quatro no grupo da RSTC. A taxa global de sucesso das restaurações foi 87,1% (85,4% para RTTC e 88,7% para RSTC) e o tempo médio de sobrevida foi de 30 meses. A taxa anual de falha foi de 7% após 24 meses de acompanhamento. Não houve diferença no risco de falha (TR) de acordo com o grupo de tratamento (TR 0,75; IC 95%: 0,38-1,46) e instituição (USP TR 0,44; IC 95%: 0,94-2,09; PERU TR 0,92; IC 95%: 0,26-3,19 EQUADOR TR 1,39; IC 95%: 0,45-4,28). Foram encontradas observações análogas em relação a todas as variáveis clínicas e demográficas. Conclusões: As restaurações adesivas realizadas em dentes decíduos com lesões cavitadas profundas em dentina apresentam sobrevida satisfatória após 33 meses de acompanhamento, independentemente da técnica realizada para remoção de tecido cariado.
The selective caries removal technique (SCR) for active deep carious lesions in deciduous and permanent teeth is already a consensus in the literature and is supported by studies that demonstrate excellent clinical, radiographic and microbiological results. However, the longevity of restorations performed after the SCR, mainly in primary dentition, has generated some doubts and concerns about its performance, deserving clarification. This multicenter study aimed to compare the success rate of adhesive restorations performed on posterior deciduous teeth after total or selective caries removal over 30 months Methods: Children between 4 - 8 years old with at least two active cavitated lesions in deep dentin (inner half of the dentin in the evaluation of the interproximal RX and with at least 1mm of dentin separating the carious lesion of the pulp) and that met the inclusion and exclusion criteria participated in the study. For each child, teeth were randomized and submitted to one of the treatment groups: total caries removal (TCR - control group) or SCR (test group). Children could have more than 2 teeth included. In cases of pulp exposure, data were analyzed and the tooth was excluded from the sample. Four institutions participated in the study (Federal University of Rio Grande do Sul, Peruvian University Cayetano Heredia and International Universidad of Ecuador), resulting in four pediatric dentists who performed the caries removal procedures and subsequent restorations in composite resin. Clinical evaluation was performed at baseline, 6, 12, 18, 24 and 30 months. All procedures were performed under local anesthesia and rubber dam use. Sociodemographic characteristics were collected at the baseline and clinical characteristics as dmft and visible plaque and gingival bleeding index were collected in all follow-up periods. Radiographs were taken only at baseline and restorations were clinically assessed at baseline, 6, 12, 18, 24 and 33 months by a blinded, trained and calibrated operator in each institution. The characteristics of the restorations were recorded according to an adaptation of the FDI criteria. Survival estimates for restoration longevity were evaluated using the Kaplan-Meier method. We also estimated the annual failure rate of the restorations. Cox regression model with shared frailty was performed to assess differences in survival rates of the restoration according to the intervention treatment, institution and clinical and demographic characteristics of the sample. Results: one hundred and six children (51 boys and 55 girls) collaborated with 278 teeth submitted to adhesive restorations (137 after TCR and 141 after SCR). Pulp exposure occurred in eight teeth (2.8%) allocated to TCR, and in four (1.4%) allocated to SCR group. The overall success rate of restorations was 87.1% (85.4% for TCR and 88.7% for SCR) and mean survival time was 30.3 months. The annual failure rate was 7% after 24 months of follow-up. There were no differences in the risk of failure according to the treatment group (HR 0.75;95%CI:0.38-1.46) and institution (USP HR 0.44;95%CI:0.94-2.09; PERU HR 0.92;95%CI:0.26-3.19; ECUADOR HR 1.39;95%CI:0.45-4.28). Analogous observations were found regarding all the clinical and demographic variables. Conclusions: Composite restorations of active deep carious lesions performed in posterior primary teeth show satisfactory survival of 87.1% after 33 months of follow-up, regardless of the technique performed for carious tissue removal.

Meta-analysis is now commonly used in medical research. However there are statistical issues relating to the subject that require investigation and some are considered here, from both a methodological and a practical perspective. Each of the fixed effect and the random effects models for meta-analysis are based on certain assumptions and the validity of these is investigated. A formal test of the homogeneity assumption made in the fixed effect model may be performed. Since the test has low power, simulation was used to investigate the power under various conditions. The random effects model incorporates a between-study component of variance into the model. A likelihood based method was used to obtain a confidence interval for this variance and also to provide an interval for the overall treatment effect which takes into account the fact that the between-study variance is estimated, rather than assuming it to be known. In order to obtain confidence intervals for the treatment effect for both the fixed effect and the random effects models, distributional assumptions of normality are usually made. Such assumptions may be checked using q-q plots of the residuals obtained for each trial in the meta-analysis. In both meta-analysis models it is assumed that the weight allocated to each study is known, when in fact it must be estimated from the data. The effect of estimating the weights on the overall treatment effect estimate, its confidence intervals, the between-study variance estimate and the test statistic for homogeneity, is investigated by both analytic and simulation methods. It is shown how meta-analysis methods may be used to analyse multicentre trials of a paired cluster randomised design. Meta-analysis techniques are found to be preferable to previously published methods specifically developed for the analysis of such designs, which produce biased and potentially misleading results when a large treatment effect is present.

The usefulness of time-to-event (survival) analysis has made it gain a wide applicability in statistically modelling research. The methodological developments of time-to-event analysis that have been widely adopted are: (i) The Kaplan-Meier method, for estimating the survival function; (ii) The log-rank test, for comparing the equality of two or more survival distributions; (m) The Cox proportional hazards model, for examining the covariate effects on the hazard function; and (iv) The accelerated failure time model, for examining the covariate effects on the survival function. Nonetheless, in time-to-event endpoints assessment, if subjects can fail from multiple mutually-exclusive causes, data are said to have competing risks. For competing risks data, the Fine and Gray proportional hazards model for sub-distributions has gained popularity due to its convenience in directly assessing the effect of covariates on the cumulative incidence function. Furthermore, sometimes competing risks data cannot be considered as independent because of a clustered design; for instance, in registry cohorts or multi-centre clinical trials. The Fine and Gray model has been extended to the analysis of clustered time-to-event data, by including random-centre effects or frailties in the sub-distribution hazard. This research focuses on the analysis of clustered competing risks with an application to the investigation of the management of pericarditis clinical trial (IMPI) dataset. IMPI is a multi- centre clinical trial that was carried out from 19 centres in 8 African countries with the principal objective of assessing the effectiveness and safety of adjunctive prednisolone and Mycobacterium indicus pranii immunotherapy, in reducing the composite outcome of death, constriction or cardiac tamponade, requiring pericardial drainage in patients with probable or definite tuberculous pericarditis. The clinical objective in this thesis is therefore to analyse time to these outcomes. In addition, the risk factors associated with these outcomes were determined, and the effect of the prednisolone and M. indcus pranii was examined, while adjusting for these risk factors and considering centres as a random effect. Using Cox proportional hazards model, it was found that age, weight, New York Heart Association (NYHA) class, hypotension, creatinine, and peripheral oedema show a statistically significant association with the composite outcome. Furthermore, weight, NYHA class, hypotension, creatinine and peripherial oedema show a statistically significant association with death. In addition, NYHA class and hypotension show a statistically significant association with cardiac tamponade. Lastly, prednisolone, gender, NYHA class, tachycardia, haemoglobin level, peripheral oedema, pulmonary infiltrate and HIV status show a statistically significant association with constriction. A value of 0.1 significance level was used to identify variables as significant in the univariate model using forward stepwise regression method. The random effect was found to be significant in the incidence of composite outcomes of death, cardiac tamponade and constriction, and in the individual outcome of constriction, but this only slightly changed the estimated effect of the covariates as compared to when the random effect was not considered. Accounting for death as a competing event to the outcomes of cardiac tamponade or constriction, does not affect the effect of the covariates on these outcomes. In addition, in the multivariate models that adjust for other risk factors, there was no significant difference in the primary outcome between patients who received prednisolone, and those who received placebo, or between those who received M. indicus pranii immunotherapy, and those who received placebo.

La qualité des données est une préoccupation fondamentale de la recherche clinique. Pour garantir cette qualité, il faut pratiquer un monitorage continu des données. Les organismes internationaux de régulation des médicaments recommandent que ce monitorage soit ciblé, basé sur une analyse des risques. De cette recommandation a germé le concept de « monitoring statistique centralisé » (MSC) qui consiste à détecter des distributions de variables atypiques dans un centre par rapport aux autres centres. Cette thèse recense les méthodes de MSC existants, en propose de nouvelles, et compare les performances des unes et des autres. Dans la première partie, nous rappelons l’intérêt du sujet, dans un contexte marqué par l’accroissement du nombre d’essais cliniques, la nécessité de travailler de plus en plus à distance et le besoin de nouveaux paradigmes de monitorage. Dans la seconde partie, nous recensons les méthodes de MSC existantes, analysons leurs performances rapportées dans la littérature et en tirons deux observations majeurs : (i) le nombre de méthodes est limité; (ii) leurs évaluations par des travaux de simulations et des applications sur données réelles rapportées dans la littérature sont également limitées. Dans la troisième partie nous proposons deux nouvelles méthodes de MSC pour détecter les distributions de variables atypiques dans les essais multicentriques, l’une pour données quantitatives qui utilise une mesure de distance standardisée (méthode de la Distance) et l’autre pour données catégorielles, qui utilise un modèle Bayésien hiérarchique bêta-binomial (HBBB). Nous évaluons les performances de ces méthodes en utilisant des simulations d'essais cliniques, puis les comparons à d’autres méthodes de MSC identifiées dans la littérature. Pour les données quantitatives, la méthode de la Distance a des performances similaires à la méthode proposée par Desmet et al., et supérieures à celles des deux autres méthodes existantes. Pour les données catégorielles, la méthode HBBB a des performances similaires à la seule autre méthode existante, également proposée par Desmet et al. Pour les deux méthodes, Distance et HBBB, la sensibilité est globalement médiocre, mais la spécificité excellente, y compris dans de nombreux scénarios impliquant de petits effectifs. La sensibilité faible suggère que le MSC est un outil supplémentaire pouvant être utilisé en complément des autres procédures de monitoring conventionnelles, mais ne les remplace pas. La spécificité forte et le caractère convivial suggère que ces méthodes peuvent être appliquées en routine dans tous les essais cliniques, car leur utilisation ne prendra pas beaucoup de temps au niveau central et n'engendrera pas de charge de travail inutile dans les centres investigateurs
Data quality is a fundamental concern of clinical research. To ensure this quality, continuous data monitoring must be practiced. International drug regulatory bodies recommend that this monitoring be targeted, based on a risk analysis. From this recommendation emerged the concept of “centralized statistical monitoring” (CSM) which consists of detecting atypical distributions of variables in a center compared to other centers. This thesis identifies existing CSM methods, proposes new ones, and compares the performances of each. In the first part, we recall the interest of the subject, in a context marked by the increase in the number of clinical trials, the need to work increasingly remotely and the need for new monitoring paradigms. In the second part, we identify existing CSM methods, analyze their performances reported in the literature and draw two major observations: (i) the number of methods is limited; (ii) their assessments through simulation studies and applications on real data reported in the literature are also limited. In the third part we propose two new CSM methods to detect the distributions of atypical variables in multicenter trials, one for quantitative data which uses a standardized distance measure (Distance method) and the other for categorical data, which uses a hierarchical Bayesian beta-binomial (HBBB) model. We evaluate the performance of these methods using clinical trial simulations and then compare them to other CSM methods identified in the literature. For quantitative data, the Distance method has performances similar to the method proposed by Desmet et al., and superior to those of the two other existing methods. For categorical data, the HBBB method has similar performance to the only other existing method, also proposed by Desmet et al. For both methods, Distance and HBBB, the sensitivity is poor overall, but the specificity is excellent, including in many scenarios involving small sample sizes. The low sensitivity suggests that the CSM is an additional tool that can be used in addition to other conventional monitoring procedures, but does not replace them. The strong specificity and user-friendliness suggest that these methods can be routinely applied in all clinical trials, as their use will not be centrally time consuming and will not create unnecessary workload in investigational centers

Proportional hazards models are among the most popular regression models in survival analysis. Multi-state models generalise them in the sense of jointly considering different types of events along with their interrelations, whereas frailty models introduce random effects to account for unobserved risk factors, possibly shared by groups of subjects. The integration of frailty and multi-state methodology is interesting to control for unobserved heterogeneity in presence of complex event history structures, particularly appealing in multicenter clinical trials applications. In the present thesis we propose the incorporation of nested frailties in the transition-specific hazard function; then, we develop and evaluate both parametric and semi-parametric inference. Simulation studies, performed thanks to an innovative method for generating dependent multi-state survival data, show that parametric inference is correct but extremely imprecise, whilst semiparametric methods are very competitive to evaluate the effect of covariates. Two case studies are presented, relative to cancer multicenter clinical trials. The multi-state nature of the models allows to study the treatment effect taking into account intermediate events, while the presence of frailties reduces the attenuation effect due to clustering. Finally, we present two new software tools, one to fit parametric frailty models with up to twenty possible combinations of baseline and frailty distributions, and one implementing semiparametric inference for multilevel frailty models, essential to fit the new nested frailty multi-state models.
I modelli a rischi proporzionali sono tra i modelli di regressione più conosciuti ed utilizzati in analisi di sopravvivenza. In modelli multi-stato sono una loro generalizzazione che permette di considerare congiuntamente diversi tipi di eventi e le loro interrelazioni, mentre i modelli di tipo frailty introducono effetti casuali per tenere conto di fattori di rischio non osservati, eventualmente in comune tra soggetti appartenenti allo stesso gruppo. L’integrazione dei modelli multi-stato e dei modelli frailty è interessante al fine di controllare l’eterogeneità non osservata in presenza di strutture complesse di eventi, particolarmente interessante nel caso di studi clinici multicentro. In questa tesi proponiamo di incorporare frailty annidati nella funzione di rischio transizione-specifica, quindi sviluppiamo e valutiamo metodi di inferenza sia parametrica che semiparametrica. Studi di simulazione, effettuati grazie a un metodo innovativo per generare dati di sopravvivenza multi-stato dipendenti, mostrano che l’inferenza parametrica è corretta ma estremamente imprecisa, mentre i metodi semiparametrici sono molto competitivi per valutare l’effetto delle covariate. Due casi-studio relativi a studi clinici multicento in oncologia vengono quindi presentati. La natura multi-stato dei modelli permette di studiare l’effetto del trattamento tenendo conto degli eventi intermedi, mentre la presenza di frailty riduce l’effetto di attenuazione dovuto ai gruppi di pazienti. Infine, presentiamo due nuovi strumenti software, uno per stimare modelli frailty parametrici con fino a venti possibili combinazioni di distribuzioni baseline e frailty, e un altro che implementa metodi di inferenza semiparametrica per modelli frailty multilivello, essenziali per stimare i nuovi modelli multi-stato con frailty annidati.

The general aims of the thesis were to study GH responsiveness by estimation of pharmacokinetics and bioavailability of injected recombinant human GH (rhGH), of growth response as gain in heightSDS during childhood and puberty, and IGF-I response as change in circulating IGF-ISDS and IGFBP3SDS. Methods Short children were recruited during 1988–1999 into two national randomized multicentre clinical trials on growth until adult height. A group of 117 GHD patients who had been treated from prepuberty with a single GH dose of 33μg/kg/day for at least 1 year were randomized at onset of puberty either to remain on this dose regimen or to an increased dose, GH67μg/kg/day, administered once daily or divided into two doses, GH33x2μg/kg/day. Data on IGF-ISDS and IGF binding protein 3 (IGFBP3)SDS were available from 111 patients and analysed as stated below. The 151 short prepubertal non-GHD patients were randomized into three groups: untreated controls, GH33 or GH67μg/kg/day. A subpopulation from both trials, 128 patients examined annually in Gothenburg, formed the study sample on GH uptake. They received sc GH injections to obtain 16–24 hour GH curves and the GH pharmacokinetics and bioavailability was calculated. Results: A dose-dependent effect on Cmax was found with great intra- and inter-individual variability. Of the Cmax variability, 43% was explained by the rhGH dose and proxies for injection depth. Median bioavailability of the injected dose was 71%, with great variation, mainly dependent on injection depth. In the IGHD group a dose-dependent difference in pubertal gain in heightSDS was found, with mean of 0.8 for the GH67 group and 0.4 for GH33, p<0.01. The mean total gain in heightSDS during treatment was 1.9 for GH67 and 1.4 for GH33, p<0.01. A dose-dependent pubertal ΔIGF-ISDS was 0.5 vs −0.1, p=0.007, correlating to pubertal gain in heightSDS, p=0.003; and was the most important variable to explain the variation in pubertal gain in heightSDS. In the non-GHD group the ΔIGF-ISDS from baseline to mean study level was dose-dependent 2.07 vs 1.20, p=0.001; and correlated negatively with baseline values of IGF-ISDS, rho= -0.56 for GH67, p=0.001, vs rho= -0.82 for GH33, p=0.0001, and correlated positively with gain in heightSDS in both GH-treated groups, rho= 0.42, p<0.001. In multivariable regression analyses, ΔIGF-ISDS was always an important explanatory variable for long-term growth response from the prepubertal period until adult height, while the IGF-ISDS study level per se was not. Conclusion: Growth response to GH treatment was dose dependent with great variability between patients. More pubertal growth was attained by an increased rhGH dose, mimicking the physiology of healthy children, in whom GH secretion rate increases during puberty. This resulted in a gain in IGF-ISDS closely correlating to pubertal gain in heightSDS in both IGHD and non-GHD patients. A broad range in GH responsiveness was found for both growth and IGF response in both diagnostic groups, but lower in the non-GHD group. Higher uptake of a given GH dose was observed after a deep injection and a higher GH concentration. These results are clinically applicable for individuals who remain short close to onset of puberty; by identifying and deeply injecting a rhGH dose that accounts for individual responsiveness, we can stimulate an increment in IGF-ISDS that correlates to gain in heightSDS during puberty.

Aim: To examine the relationship between reported vigorous physical activity (VPA) and body mass index (BMI) in children (6–7 years) and adolescents (13–14 years). Methods: In the International Study of Asthma and Allergies in Childhood Phase Three, 75 895 children's parents and 199 502 adolescents answered questions relating to VPA, height and weight. The association between VPA and BMI was analysed using general linear models, adjusting for country gross national index. Results: Compared to children who undertook no VPA, those in the infrequent group (once or twice per week) and those in the frequent group (three or more times per week) had mean (95% CI) BMI values 0.07 kg/m 2 (0.03–0.11) and 0.09 kg/m 2 (0.03–0.15) greater, respectively (p = 0.001). Compared to adolescents reporting no VPA, those in the infrequent group had a BMI 0.19 kg/m 2 (0.15–0.23) greater while those in the frequent group had a BMI 0.01 kg/m 2 (−0.03–0.05) greater (p < 0.0001). Conclusion: Reported VPA is not associated with lower BMI among children and adolescents. Investigation of VPA and BMI may be best undertaken in conjunction with other variables in the energy expenditure equation. A focus on VPA alone may be an inefficient way to manage BMI.
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L’ictus rappresenta la seconda causa di morte a livello globale e la prima causa di disabilità negli anziani. A causa di alcuni limiti di impiego, le principali terapie disponibili, volte a ripristinare il flusso sanguigno attraverso fibrinolisi e/o trombectomia meccanica, possono essere usate solo nel 60% dei pazienti con eziologia ischemica. Per tale motivo, la ricerca preclinica cerca di identificare target terapeutici utili per definire nuovi trattamenti ed estendere l’accesso alle cure. Nessuna nuova strategia terapeutica identificata negli studi preclinici ha però confermato la sua efficacia nei trial clinici. I problemi di traslazionalità dipendono da alcuni limiti degli studi preclinici, come l’uso di un ridotto numero di animali, che non rappresentano le condizioni reali dei pazienti o la mancata replicazione dei risultati ottenuti dai singoli laboratori, introducendo così bias metodologici, tra cui la mancanza di protocolli armonizzati. Il presente studio origina dalla necessità di migliorare il valore traslazionale della ricerca preclinica nell’ictus ischemico attraverso la definizione di un multicentre preclinical randomised controlled trial (pRCT), il progetto TRICS, che ha l’obiettivo di valutare l’azione neuroprotettiva del remote ischemic conditioning (RIC) dopo l’evento ischemico. Perché il RIC raggiunga una neuroprotezione significativa, l’outcome primario è che induca un miglioramento dei deficit sensorimotori a 48 ore dall’evento ischemico, calcolati attraverso il De Simoni neuroscore. Lo score valuta i deficit generali, che indicano lo stato di salute dell’animale e i deficit focali selettivamente associati alle conseguenze neurologiche dell’ischemia. Per ridurre al minimo i bias tecnici, il nostro studio ha previsto una prima fase di armonizzazione della valutazione comportamentale tra i centri, mediante analisi della concordanza tra i rater che eseguivano la misura, definita come interrater agreement. Questo è stato calcolato come intraclass correlation coefficient, ICC=0, nessun accordo, a ICC=1, accordo perfetto. Ci siamo posti l’obiettivo di raggiungere un interrater agreement con un ICC≥ 0.60. Una buona concordanza tra i centri è infatti una condizione indispensabile per garantire che tutti applichino lo stesso metodo di valutazione, assicurando l’oggettività, la trasparenza e la riproducibilità dei risultati. Dopo un training sull’esecuzione del De Simoni neuroscore, ogni centro ha indotto l’ischemia cerebrale nell’animale mediante l’occlusione transiente dell’arteria cerebrale media (tMCAo). A 48 ore dall’operazione, tutti gli animali sono stati filmati durante l’esecuzione del test e i video sono stati inviati al centro coordinatore, che li ha randomizzati e inoltrati ai centri. Un rater per ogni centro ha eseguito in cieco il De Simoni neuroscore sui video e sulle valutazioni è stata eseguita l’analisi statistica. Il risultato ottenuto dall’interrater agreement è stato di ICC=0.50 (0.22-0.77) per i topi e ICC=0.49 (0.210.77) per i ratti; non siamo riusciti a raggiungere l’obiettivo prefissato. Questi risultati sono dipesi da alcuni errori nell’esecuzione del test e dall’attribuzione sbagliata dei punteggi. È stata organizzata una seconda fase di training per superare le differenze di valutazioni più evidenti e preparati nuovi animali ischemici con cui sostituire i video che presentavano errori. Il risultato ottenuto dall’interrater agreement del secondo trial è stato di ICC=0.64 (0.37 – 0.85) per i topi e ICC=0.69 (0.44 - 0.88) per i ratti, soddisfacendo quindi il criterio per iniziare la fase interventistica dello studio. La fase di armonizzazione rappresenta un nuovo ed originale approccio nella ricerca preclinica e dovrebbe rappresentare lo schema di lavoro di base per pianificare uno studio pRCT al fine di renderlo solido e predittivo.
In view of fostering transferability of pre-clinical data on the efficacy of remote ischemic conditioning (RIC) in acute ischemic stroke, we designed two multi-centre translational trials in mice and rats of both sexes. We defined to model ischaemic stroke by the transient occlusion of the middle cerebral artery (tMCAo). The improvement of sensorimotor deficits at 48h after tMCAo in RIC-treated animals was defined as the primary outcome. This work presents the harmonization phase relative to the evaluation of sensorimotor deficits by De Simoni neuroscore. Each centre performed different tMCAo durations - 30, 45, 60 min - allowing sufficient variability in the outcome. Animals were monitored post-surgery according to the ARRIVE and IMPROVE guidelines and data was registered into an electronic case report form on RedCap. All animals were video recorded during the neuroscore and the videos (n=11 per species) were distributed and evaluated blindly by raters at all centres. The interrater agreement of neuroscore was described using intraclass correlation coefficient (ICC), ranging between ICC=0 (equivalent to chance) and ICC=1 (perfect agreement), setting a target of ICC≥0.60 as satisfactory. We obtained moderate agreement for mice (ICC=0.50 [0.22-0.77]) and rats (ICC=0.49 [0.21-0.77]). Errors were identified in animal handling and test execution. We thus performed a second training followed by a new blind evaluation replacing the videos with poor experimental execution. The interrater agreement improved for mice (ICC=0.64 [0.37-0.85]) and rats (ICC=0.69 [0.44-0.88]). In conclusion, two dedicated training on the neuroscore allowed us to reach the agreement target for both species and thus next proceed with the interventional phase of the project.

The conduct of clinical trials under time constraints in the paediatric critical care setting may pose an ethical dilemma for researchers. Many life-saving interventions do not allow adequate time to obtain informed, prospective consent from parents or legal guardians. The rapid decision process in the paediatric critical care environment challenges the ethically accepted gold standard of consent prior to interventional research. In time-critical research, provision is made to obtain consent after the intervention has taken place. This concept is often referred to as deferred consent but may also be referred to as delayed consent, consent to continue, or research without prior consent. Deferred consent aims to progress critical care research by mitigating the limitations of consent faced by researchers. If the intervention pertains to the treatment of critically ill children, the use of deferred consent may be required to perform the intervention pragmatically and to capture a true representation of the study population. Without deferred consent it is possible that patients requiring an immediate life-saving intervention may be missed. This may result in selection bias thus affecting study outcomes and the generalisability of research findings. This thesis examined findings from a nested study to investigate whether differences in consent requirements led to significant differences in the study populations and outcomes of an existing multicentre, interventional, clinical trial within Paediatric Intensive Care Units. The parent trial, the Transnasal Humidified Rapid-Insufflation Ventilatory Exchange in children requiring emergent intubation (Kids THRIVE) trial, examines a system of high flow oxygen delivery during the emergency intubation of children. The Kids THRIVE Study sought approval to use deferred consent in circumstances where prospective consent was not possible. Measures of severity of illness were used to compare participants recruited to the Kids THRIVE trial using deferred consent with those recruited using prospective consent. Severity of illness was measured in ventilator hours, hospital and intensive care length of stay and PIM3 codes. Results indicate that children recruited to the Kids THRIVE trial using deferred consent differed clinically and statistically to those children recruited using prospective consent. Children in the deferred consent group were more unwell and had less favourable clinical outcomes. They were mechanically ventilated for longer (median [IQR] 70.97 [35.58-122.30]vs 48.85 [27.41-120.91] hours, P=0.001); spent longer in intensive care (median [IQR] 8.84 [4.55-18.38] vs 7.17 [4.25-14.29] days, P= 0.020); and had a longer hospital stay (median [IQR] 27.95 [12.69-63.59] vs 19.77 [10.28-39.96] days, P=0.010) than their counterparts in the prospective consent group. PIM3 scores which predict a percentage probability of death did not show any statistically significant difference between the two groups. This research provides evidence that the exclusive use of prospective consent in paediatric critical care research can lead to selection bias by recruiting a study population that is not representative of paediatric intensive care patients. Alternatives to prospective informed consent need to be considered to progress research in this patient cohort.
Thesis (Masters)
Master of Medical Research (MMedRes)
School of Pharmacy & Med Sci
Griffith Health
Full Text

Esta tese se pautou nas interfaces entre a estrutura do Sistema Nacional de Inovação em Saúde e o Sistema Nacional de Saúde - componentes estratégicos para os setores econômico e social do país. Abordou-se o marco jurídico institucional que dá sustentação à Ciência e Tecnologia em Saúde, envolvendo o arcabouço político que ampara a inovação tecnológica no país e os sistemas de regulação voltados a garantir sua sustentabilidade. O propósito desta pesquisa foi o de investigar as relações e os padrões que possibilitam o estabelecimento de vínculos entre os atores e ainda favorecem a formação de redes de pesquisas, buscando identificar quais os elementos que necessitam de maior foco dos gestores de forma que as conexões estabelecidas sejam fortalecidas e facilitem o monitoramento e a avaliação das redes. Caracteriza-se por ser uma pesquisa qualitativa elaborada a partir da teoria crítica, de abordagem quantitativa, incluindo um estudo de caso exploratório e analítico sobre a Rede Nacional de Pesquisa Clínica em Hospitais de Ensino, envolvendo a triangulação de métodos, baseada na observação, na análise de conteúdo e na vertente bibliográfica. Apoiou-se nas bases da Teoria Ator-Rede, ao investigar as relações e os padrões, que acabam por se configurar como vínculos entre pesquisadores e instituições. Os resultados depreendidos do estudo acrescentam novas compreensões sobre a gestão de redes de pesquisas, cuja análise se encontra hoje permeada por uma literatura centrada em atributos individuais. Ao se perceber a pesquisa clínica multicêntrica como estratégica fomentadora de inovação para saúde, esta tese delineou alternativas de gestão para expandir as conexões relacionais passíveis de fomentar, ampliar e fortalecer o Sistema Nacional de Ciência, Tecnologia e Inovação em Saúde e suas associações com as necessidades do Sistema Único de Saúde
This thesis is based on the interfaces between the Brazilian National System for Innovation in Health\'s structure and the Brazilian National Health System - strategic components for the economic and social sectors in the country. The institutional legal framework that gives support to Science and Technology in Health was referred to, considering the policies that sustain technological innovation in the country and the regulatory systems aimed at guaranteeing its sustainability. The goal of this study was to investigate the relationships and the patterns that make it possible to establish ties between actors and that also favor the formation of research networks, seeking to identify which elements require a greater focus from managers in order to strengthen the established ties and to facilitate network monitoring and evaluation. This study is a qualitative one that is elaborated upon critical theory, upon a quantitative approach, and includes an exploratory and analytical case study on the Brazilian National Network of Clinical Research in Teaching Hospitals, comprising a triangulation of methods, based on observation, on content analysis and on bibliographic lines. Upon investigating relationships or patterns, this study relied upon the bases of Actor-Network Theory, which result in ties formed between researchers and institutions. The results gathered from the study added new insight into the management of research networks, whose analysis is currently permeated by literature centered on individual attributes. Upon perceiving multicenter clinical trials as a strategy that fortifies innovation in health, this thesis outlined management alternatives that may expand the relational connections believed to foment, increase and strengthen the Brazilian National Science, Technology and Innovation System and its associations with Brazilian Public Health System needs

Une élévation majeure de la charge mutationnelle (hypermutation) est observée dans certains gliomes. Néanmoins, les mécanismes de ce phénomène et ses implications thérapeutiques notamment concernant la réponse à la chimiothérapie ou à l'immunothérapie sont encore mal connus. Sur le plan du mécanisme, une association entre hypermutation et mutations des gènes de la voie de réparation des mésappariements de l'ADN (MMR) a été rapportée dans les gliomes, cependant la plupart des mutations MMR observées dans ce contexte n'étaient pas fonctionnellement caractérisées, et leur rôle dans le développement d’hypermutation restait de ce fait incertain. De plus, l'impact de l'hypermutation sur l'immunogénicité des cellules gliales et sur leur sensibilité au blocage des points de contrôles immunitaires (par exemple par traitement anti-PD-1) n’est pas connu. Dans cette étude, nous analysons de manière exhaustive les déterminants cliniques et moléculaires de la charge et des signatures mutationnelle dans 10 294 gliomes, dont 558 (5,4%) tumeurs hypermutées. Nous identifions deux principales voies responsables d'hypermutation dans les gliomes : une voie "de novo" associée à des déficits constitutionnels du système MMR et de la polymérase epsilon (POLE), ainsi qu'une voie "post-traitement", plus fréquente, associée à l'acquisition de déficits MMR et de résistance secondaire dans les gliomes récidivant après chimiothérapie par temozolomide. Expérimentalement, la signature mutationnelle des gliomes hypermutés post-traitement (signature COSMIC 11) était reproduite par les dommages induits par le témozolomide dans les cellules MMR déficientes. Alors que le déficit MMR s'associe à l'acquisition de résistance au témozolomide, des données cliniques et expérimentales suggèrent que les cellules MMR déficientes conservent une sensibilité à la nitrosourée lomustine. De façon inattendue, les gliomes MMR déficients présentaient des caractéristiques uniques, notamment l'absence d'infiltrats lymphocytaires T marqués, une hétérogénéité intratumorale importante, une survie diminuée ainsi qu’un faible taux de réponse aux traitements anti-PD-1. De plus, alors que l'instabilité des microsatellites n'etait pas détectée par des analyses en bulk dans les gliomes MMR déficients, le séquençage du génome entier à l'échelle de la cellule unique de gliome hypermuté post-traitement permettait de démontrer la presence de mutations des microsatellites. Collectivement, ces résultats supportent un modèle dans lequel des spécificités dans le profil mutationnel des gliomes hypermutés pourraient expliquer l’absence de reconnaissance par le système immunitaire ainsi que l’absence de réponse aux traitements par anti-PD-1 dans les gliomes MMR déficients. Nos données suggèrent un changement de pratique selon lequel la recherche d’hypermutation par séquençage tumoral lors de la récidive après traitement pourrait informer le pronostic et guider la prise en charge thérapeutique des patients
High tumor mutational burden (hypermutation) is observed in some gliomas; however, the mechanisms by which hypermutation develops and whether it predicts chemotherapy or immunotherapy response are poorly understood. Mechanistically, an association between hypermutation and mutations in the DNA mismatch-repair (MMR) genes has been reported in gliomas, but most MMR mutations observed in this context were not functionally characterized, and their role in causing hypermutation remains unclear. Furthermore, whether hypermutation enhances tumor immunogenicity and renders gliomas responsive to immune checkpoint blockade (e.g. PD-1 blockade) is not known. Here, we comprehensively analyze the clinical and molecular determinants of mutational burden and signatures in 10,294 gliomas, including 558 (5.4%) hypermutated tumors. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and MMR genes, and a more common, post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas recurring after temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas (COSMIC signature 11) was recapitulated by temozolomide-induced damage in MMR-deficient cells. While MMR deficiency was associated with acquired temozolomide resistance in glioma models, clinical and experimental evidence suggest that MMR-deficient cells retain sensitivity to the chloroethylating nitrosourea lomustine. MMR-deficient gliomas exhibited unique features including the lack of prominent T-cell infiltrates, extensive intratumoral heterogeneity, poor survival and low response rate to PD-1 blockade. Moreover, while microsatellite instability in MMR-deficient gliomas was not detected by bulk analyses, single-cell whole-genome sequencing of post-treatment hypermutated glioma cells demonstrated microsatellite mutations. Collectively, these results support a model where differences in the mutation landscape and antigen clonality of MMR-deficient gliomas relative to other MMR-deficient cancers may explain the lack of both immune recognition and response to PD-1 blockade in gliomas. Our data suggest a change in practice whereby tumor re-sequencing at relapse to identify progression and hypermutation could inform prognosis and guide therapeutic management

碩士
長庚大學
醫學影像暨放射科學系
100
18F-AV-45 and 18F-AV-133 are novel PET tracers for imaging the deposition of amyloid in Alzheimer’s disease and the VMAT2 in dopaminergic neuron degeneration of Parkinson’s disease, respectively. For the purpose of observing the disease progression and the need in clinical diagnosis, we can widely investigate the variation between the control and diseased groups by collecting the data from the multicenter clinical trials. To establish the index of quality control assessment to evaluate the image quality in multicenter clinical trials was the first goal in this thesis. Then, in order to achieve comparability and interchangeability of information from different scanning systems, correcting the variation among images and data conversion from different scanners are the second focus in this thesis. Here, to correct the variation and reduce the variability between images, studies were performed using Hoffman phantom by first evaluating the resolution kernel for each system, and then applying smoothing filters to reduce high-frequency variability. In addition, study using the striatal phantom was used to derive the transformation factor for data conversion in PET images, and using another phantom data to validate the performance of the data conversion. The results demonstrated that all images passed the criteria of quality control assessment. The derived FWHM kernels in high-frequency correction can reduce the variability and increase the comparability between scanners. With the application of the transformation factor, a minor percentage difference between scanners is shown in the retest phantom data. To evaluate its capability, the factor is also applied to the clinical data, and the result shows consistency with those in the phantom study. But for the severely declined area, a specific transformation factor should be used. In conclusion, by applying the FWHM kernels in high frequency correction can reduce the variation between scanners, and make images comparable. Also, the derived transformation factor can be applied for data conversion between scanners.